Abstract
Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. It is a prodrug that is converted by several cytochrome P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Antidepressants (ADs), which are often coprescribed to patients receiving tamoxifen, are also metabolized by CYP2D6 and evidence suggests that a drug–drug interaction between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. We evaluated this potentially important drug–drug interaction in vivo in mice humanized for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLMs) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes. Coincubation with quinidine, a CYP2D6 inhibitor, ablated endoxifen generation by hCYP2D6 MLMs. The NDT-hydroxylation activity of wild-type MLMs was 7.4 times higher than that of hCYP2D6, whereas MLMs from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the human liver microsome panel. In vitro, ADs of the selective serotonin reuptake inhibitor class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLMs than were compounds of the tricyclic class. At a clinically relevant dose, paroxetine pretreatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy.
Highlights
Tamoxifen has been approved for clinical use for over 40 years, only recently has it been identified as a potential prodrug
Liver microsomes from Cyp2dKO mice did not produce detectable levels of endoxifen, whereas liver microsomes from wild-type mice produced 7.4-fold more endoxifen than humanized for CYP2D6 (hCYP2D6) liver microsomes
Tamoxifen has been in clinical use for the treatment of cancer since the 1970s but the relatively recent discovery of endoxifen (Stearns et al, 2003), coupled with an increased understanding of the phenotypic variability of CYP2D6 (Zanger et al, 2004), has suggested opportunities for further optimization of therapy
Summary
Tamoxifen has been approved for clinical use for over 40 years, only recently has it been identified as a potential prodrug. Two hydroxylated metabolites in particular, endoxifen and 4-hydroxytamoxifen (4-HT), have been shown to be up to 100 times more potent estrogen receptor (ER) antagonists than the parent compound (Johnson et al, 2004) and are likely to contribute to target inhibition and, thereby, the outcome of therapy (Fig. 1). Because endoxifen is several times more abundant in systemic blood samples than 4-HT, it is generally considered the more important of these metabolites (Stearns et al, 2003; Madlensky et al, 2011). Phenotypic status with regard to this enzyme profoundly influences the circulating level of endoxifen at steady state (Stearns et al, 2003; Mürdter et al, 2011). A meta-analysis by the International Tamoxifen Pharmacogenomics Consortium found, when strict inclusion
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